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Resistance is futile: A CRISPR homing gene drive targeting a haplolethal gene

View ORCID ProfileJackson Champer, Emily Yang, Yoo Lim Lee, View ORCID ProfileJingxian Liu, Andrew G. Clark, View ORCID ProfilePhilipp W. Messer
doi: https://doi.org/10.1101/651737
Jackson Champer
Department of Computational Biology, Cornell University, Ithaca, NY 14853Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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  • For correspondence: jc3248@cornell.edu messer@cornell.edu
Emily Yang
Department of Computational Biology, Cornell University, Ithaca, NY 14853Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Yoo Lim Lee
Department of Computational Biology, Cornell University, Ithaca, NY 14853Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Jingxian Liu
Department of Computational Biology, Cornell University, Ithaca, NY 14853Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Andrew G. Clark
Department of Computational Biology, Cornell University, Ithaca, NY 14853Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Philipp W. Messer
Department of Computational Biology, Cornell University, Ithaca, NY 14853
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  • ORCID record for Philipp W. Messer
  • For correspondence: jc3248@cornell.edu messer@cornell.edu
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ABSTRACT

Engineered gene drives are being explored as a potential strategy for the control of vector-borne diseases due to their ability to rapidly spread genetic modifications through a population. While an effective CRISPR homing gene drive for population suppression has recently been demonstrated in mosquitoes, formation of resistance alleles that prevent Cas9 cleavage remains the major obstacle for drive strategies aiming at population modification, rather than elimination. Here, we present a homing drive in Drosophila melanogaster that reduces resistance allele formation below detectable levels by targeting a haplolethal gene with two gRNAs while also providing a rescue allele. This is because any resistance alleles that form by end-joining repair will typically disrupt the haplolethal target gene, rendering the individuals carrying them nonviable. We demonstrate that our drive is highly efficient, with 91% of the progeny of drive heterozygotes inheriting the drive allele and with no resistance alleles observed in the remainder. In a large cage experiment, the drive allele successfully spread to all individuals. These results show that a haplolethal homing drive can be a highly effective tool for population modification.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 27, 2019.
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Resistance is futile: A CRISPR homing gene drive targeting a haplolethal gene
Jackson Champer, Emily Yang, Yoo Lim Lee, Jingxian Liu, Andrew G. Clark, Philipp W. Messer
bioRxiv 651737; doi: https://doi.org/10.1101/651737
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Resistance is futile: A CRISPR homing gene drive targeting a haplolethal gene
Jackson Champer, Emily Yang, Yoo Lim Lee, Jingxian Liu, Andrew G. Clark, Philipp W. Messer
bioRxiv 651737; doi: https://doi.org/10.1101/651737

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